PROJECT 1 ? SUMMARY Uncontrolled tumor growth (cancer) often results as a consequence of a patient's ineffective immune responses against the tumor. Cancer immunotherapy aims at restoring the body's defense system with tumor- specific immune responses. Since dendritic cells (DCs) are professional antigen-presenting cells that can process and present tumor antigen to T cells to initiate immune responses, DC vaccines are the natural choice for therapeutic intervention. Approval by the US Food and Drug Administration of sipuleucel-T, a DC vaccine for advanced prostate cancer, represented a major milestone in this promising field. A DC vaccine is usually comprised of DCs internalized with tumor antigens and adjuvants. A sequence of physical and biological events determine the success of a functional DC vaccine to elicit the proper immune responses: 1) The DC vaccine must migrate from the injection site to lymphoid tissues; 2) The DC vaccine must maintain a mature stimulatory status to persistently process and present the immunizing antigen to T cells; and 3) The antigen-specific T cells must travel to the tumor-bearing organ and infiltrate into the tumor microenvironment to exert their anti-tumor activity. However, these events are often insurmountable hurdles for most DC vaccines thus far. Clinical studies have shown that only less than 5% of intradermally injected DCs can reach the lymph nodes. In addition, the stimulatory signals of ex vivo matured DCs cannot be maintained in vivo. Furthermore, the tumor microenvironment prevents infiltration of the cytotoxic T cells. Therefore, overcoming these sequential barriers is critical to the development of a successful therapeutic DC vaccine, in order to facilitate effective transport of the DC vaccine and activated T cells. For Project 1 of the Center for Immunotherapeutic Transport Oncophysics (CITO), we hypothesize that successful negotiation of the sequential physical and biological barriers determines accumulation of DC vaccine in the lymph nodes, especially the tumor-draining lymph nodes. Also, modification of the tumor microenvironment facilitates transport of the effector T cells and macromolecular drugs that synergize with the Nano-DC vaccine for effective cancer therapy. We have developed a HER2-specific Nano-DC vaccine to test the hypothesis. The cell surface HER2 protein is expressed in approximately 20-30% of breast cancers and also in many pancreatic cancer patients. We have recently developed a porous silicon microparticle (PSM)-based platform for DC vaccine (Nano-DC vaccine) development, and demonstrated that PSM could serve both as a reservoir for the tumor antigen and as an adjuvant to stimulate the DC cells. We will apply the Nano-DC vaccine platform in this study, and will test our hypothesis in murine models of breast cancer. The project will be tightly integrated with the Transport Oncophysics Core (TOC) hinging on its imaging, quantification, analysis, and computational transport modeling services to enable precision immunotherapy.